Although nicotine is not the primary driver of tobacco-related diseases, it is biologically active and not harmless. Nicotine increases oxidative stress and systemic inflammation, damages endothelial function, and activates the sympathetic nervous system, resulting in increased heart rate, blood pressure, and myocardial oxygen demand. Chronic exposure promotes platelet aggregation, insulin resistance, dyslipidemia, and atherosclerosis, all of which contribute to cardiovascular disease risk. These effects are relevant regardless of the route of delivery and are particularly concerning with frequent or high-dose exposure.⁴

With the rise of nicotine pouches, patterns of misuse such as “pouch stacking” (using multiple pouches sequentially or simultaneously) have been increasingly reported. This behavior can result in nicotine doses comparable to or exceeding those from heavy cigarette smoking, with reported cases of nicotine toxicity presenting with nonspecific symptoms such as nausea, hypertension, and seizures. ^{5, 6}

Nicotine pouches are marketed as tobacco-free and smoke-free alternatives. However, pharmacokinetic studies demonstrate that some high-strength pouches deliver plasma nicotine concentrations comparable to, or exceeding, those achieved with cigarettes, particularly with repeated use or higher doses.⁷ Acute studies show dose-dependent increases in heart rate and blood pressure in both smokers and non-smokers.⁸

Long-term cardiovascular risk data are largely extrapolated from snus studies, which show increased all-cause and cardiovascular mortality even among lower-intensity users.⁸ Persistently elevated heart rate is an independent risk factor for cardiovascular morbidity and mortality, suggesting that chronic oral nicotine exposure may have clinically meaningful long-term effects.

Electronic cigarettes remain challenging to evaluate due to substantial heterogeneity in device design, power output, e-liquid composition, and user behavior. Higher wattage devices deliver significantly greater nicotine doses and generate higher levels of toxic aldehydes and volatile organic compounds. User behaviors such as high-intensity puffing further increase exposure, even with lower-nicotine formulations.⁹

Both nicotine-containing and nicotine-free vaping aerosols have been associated with endothelial dysfunction, increased arterial stiffness, oxidative stress, and platelet activation, suggesting that non-nicotine components also contribute to cardiovascular risk.⁹  Pulmonary complications linked to vaping include EVALI, asthma exacerbations, chronic bronchitis, bronchiolitis obliterans, and inflammatory lung disease, with long-term outcomes still poorly defined.¹⁰

Youth uptake remains a major concern. E-cigarettes have become the most commonly used nicotine product among U.S. adolescents, driven by flavorings, device innovation, and misperceptions of safety. Earlier initiation increases the likelihood of long-term dependence and progression to sustained nicotine use.

Heated tobacco products reduce exposure to some combustion-related toxicants but still deliver nicotine and other harmful constituents. Independent studies demonstrate adverse effects on vascular function, airway responsiveness, and cellular integrity, though generally at lower levels than combustible cigarettes.¹¹ Long-term health outcomes remain uncertain, and industry-independent evidence is limited.

Smoked and vaporized cannabis creates combustion products and airway irritants associated with chronic bronchitis, airway inflammation, and bullous lung disease. Dual use with nicotine is common and associated with greater dependence and additive respiratory and mental health risks. ^12-14 Vaporized cannabis can deliver high Tetrahydrocannabinol (THC) doses rapidly, increasing the risk of acute psychiatric and cardiovascular effects, particularly in younger users. ^{13, 15}

While overall all-cause mortality appears lower than with tobacco, inhaled cannabis is not risk-free, and emerging evidence links cannabis use disorder with increased head and neck cancer risk.^{16, 17}